Schaffrath Raffael, Abdel-Fattah Wael, Klassen Roland, Stark Michael J R
Department of Genetics, University of Leicester, Leicester, LE1 7RH, UK; Institut für Biologie, Abteilung Mikrobiologie, Universität Kassel, 34132, Kassel, Germany.
Mol Microbiol. 2014 Dec;94(6):1213-26. doi: 10.1111/mmi.12845. Epub 2014 Nov 17.
Diphthamide is a conserved modification in archaeal and eukaryal translation elongation factor 2 (EF2). Its name refers to the target function for diphtheria toxin, the disease-causing agent that, through ADP ribosylation of diphthamide, causes irreversible inactivation of EF2 and cell death. Although this clearly emphasizes a pathobiological role for diphthamide, its physiological function is unclear, and precisely why cells need EF2 to contain diphthamide is hardly understood. Nonetheless, the conservation of diphthamide biosynthesis together with syndromes (i.e. ribosomal frame-shifting, embryonic lethality, neurodegeneration and cancer) typical of mutant cells that cannot make it strongly suggests that diphthamide-modified EF2 occupies an important and translation-related role in cell proliferation and development. Whether this is structural and/or regulatory remains to be seen. However, recent progress in dissecting the diphthamide gene network (DPH1-DPH7) from the budding yeast Saccharomyces cerevisiae has significantly advanced our understanding of the mechanisms required to initiate and complete diphthamide synthesis on EF2. Here, we review recent developments in the field that not only have provided novel, previously overlooked and unexpected insights into the pathway and the biochemical players required for diphthamide synthesis but also are likely to foster innovative studies into the potential regulation of diphthamide, and importantly, its ill-defined biological role.
白喉酰胺是古菌和真核生物翻译延伸因子2（EF2）中一种保守的修饰。其名称源于白喉毒素的靶标功能，白喉毒素作为致病因子，通过对白喉酰胺进行ADP核糖基化，导致EF2不可逆失活并引发细胞死亡。尽管这清楚地强调了白喉酰胺的病理生物学作用，但其生理功能尚不清楚，而且细胞为何需要EF2含有白喉酰胺也几乎不为人知。尽管如此，白喉酰胺生物合成的保守性以及无法合成白喉酰胺的突变细胞所具有的典型综合征（即核糖体移码、胚胎致死、神经退行性变和癌症）强烈表明，白喉酰胺修饰的EF2在细胞增殖和发育中占据着重要的与翻译相关的作用。这是结构上的作用还是调节作用仍有待观察。然而，最近在剖析出芽酵母酿酒酵母的白喉酰胺基因网络（DPH1 - DPH7）方面取得的进展，显著推进了我们对在EF2上启动和完成白喉酰胺合成所需机制的理解。在此，我们综述该领域的最新进展，这些进展不仅为白喉酰胺合成途径及所需的生化作用因子提供了新颖的、之前被忽视的和意想不到的见解，而且还可能促进对白喉酰胺潜在调节作用以及重要的是其尚不明确的生物学作用的创新性研究。
